Various synthetic peptides identified by peptide library screening with soluble extracellular ligand binding domain of EGF-receptor (sEGFR) as a specific probe will be analyzed for their capacity to bind to the EGF- receptor on living cells and to modulate receptor functions. These include, inhibition of EGF binding, inhibition of EGF-receptor dimerization and determination of binding constants towards EGF-receptor from quantitative binding experiments. Moreover, the capacity of the synthetic peptides to either inhibit or activate EGF receptor will be analyzed including, EGF-receptor tyrosine kinase activity, substrate phosphorylation, receptor internalization and down regulation, DNA synthesis and transformation. the synthetic peptides will be also tested for their capacity to block the proliferation of tumor cell lines which overexpress EGF-receptor and respond to EGF. Feedback of these results to other components of the NCDDG will result in generation of additional peptides which will be also analyzed for their binding properties and biological activities. The analysis of the molecular pharmacology of the peptides which bind to EGF-receptor will be extended to other receptor systems. For these systems, Dr. Ullrich component of this project will provide additional soluble receptors. the Arizona component will generate and identify synthetic peptides which will be tested and optimized in our laboratory. Our NCDDG component which focuses on investigation of receptor binding properties of the synthetic peptides and their capacity to influence signal transduction pathways will play an important role in our overall program to develop receptor based peptide antagonists for human tumors.